having a complete response. Te higher dose of ide-cel provided a higher frequency of patients with 81% of patients receiving that regimen having a response, with 39% having complete response. Te estimated median duration of response was 10.7 months. Estimated progression-free survival was 8.8 months and median overall survival was 19.4 months. KarMMa supported ide-cel 150 X 106 to 450 x 106 CAR-T+ cells are effective, with the higher dose seeming to be more effective. KarMMa-3, an open-label phase 3 trial,


compared ide-cel to standard regimens for patients with triple-class exposed, relapsed and refractory MM who had received two to four lines of therapy and disease refractory to last regimen (n = 386). Standard regimen choice was at the discretion of the treating physician and included: daratumumab/pomalidomide/ dexamethasone (DPd), daratumumab/ bortezomib/dexamethasone (DVd), ixazomib/lenalidomide/dexamethasone (IRd), carfilzomib/dexamethasone, and elotuzumab/pomalidomide/dexamethasone. Patients receiving ide-cel could receive bridging therapy at investigator discretion. Compared with patients in KarMMa, those included in KarMMa-3 were earlier in their disease course with an average duration of disease of four years and had trialed three prior treatment lines. Progression-free survival was 13.3 months in the ide-cel group compared to 4.4 months in the standard of care group, HR 0.49 (95%CI, 0.38-0.65). Overall response was 71% in the ide-cel group and 42% in the standard of care, OR 3.47 (95%CI, 2.24-5.39). Complete response favored ide-cel as well with 39% versus 5% with standard of care. Te median time to response was 2.9 months in patients receiving ide-cel versus 2.1 months in the standard of care group. KarMMa-3 showed ide-cel therapy in comparison with standard of care resulted in longer progression-free survival. Te most common adverse reactions


reported for ide-cel include cytopenias, febrile neutropenia, infections, cytokine release syndrome (CRS), hypogammaglobulinemia, and muscle- skeletal pain. CRS occurred in 89% of patients treated with ide-cel in KarMMa


and KarMMa-3, with Grade 3 and above occurring in 7% of patients. Te median time to onset was one day with a duration lasting five days. Te manufacturer recommends keeping at least two doses of tocilizumab on hand prior to administration of CAR-T for MM to treat CRS, due to 65% of patients requiring at least one dose. Immune-effector cell-associated neurotoxicity (ICANS) commonly occurs concurrently with CRS. It can present as encephalopathy, headache, dizziness, tremor, and delirium. ICANS occurred in 40% of patients with a median onset of two days with a duration of eight days. CARTITUDE-1, an open-label single-


arm phase 1b/2 study, assessed safety and efficacy of cilta-cel in patients with refractory MM that had received at least three prior lines of treatment that included an immune modulator agent, proteasome inhibitor, and anti-CD38 antibody or were double refractory to an immune modulator agent and proteasome inhibitor. Patients recruited and received cilta-cel at the recommended phase 2 dose (n = 97) on average were 61 years old, had received six prior lines of treatment, had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (96%), diagnosed for 5.9 years, and received bridging therapy between apheresis and cilta-cel infusion (75%). Choice of bridging therapy was leſt up to the treating physician although it had to be approved by the study sponsor. Overall response at an average of 12.4 months was 97% with 67% of patients having a complete response. Te median time to response was one month with 79% of patients having a response. Overall survival rate at 12 months was 89%, with progression- free survival at 77%. CARTITUDE-1 was able to confirm early and efficacious responses in patients with refractory MM. CARTITUDE-4, an open-label


randomized controlled phase 3 study, compared cilta-cel to the standard of care regimens of pomalidomide/bortezomib/ dexamethasone (PVd) or DPd in patients with MM refractory to lenalidomide and had received one to three lines of treatment (n = 419). All patients randomized to the cilta-cel group received bridging therapy with PVd or DPd. Compared to the phase 1b/2 CARTITUDE-1 patients, the phase-3


CARTITUDE-4 patients were earlier in their disease course with an average duration of disease of three years. At 12 months, progression-free survival was 75.9% in the cilta-cel group and 48.6% in the standard of care group. Complete response or better at 12 months favored the cilta-cel group with 73.1% versus 21.8% in the standard of care group RR 2.9 (95%CI, 2.3-3.7). Furthermore, among patients with a response, 84.7% of the cilta-cel group and 63% of the standard of care continued to have a response for at least 12 months. In summary, CARTITUDE-4 further confirmed cilta-cel's efficacy, showing a lower risk of disease progression with cilta- cel when compared to standard of care. Te common adverse events with cilta-


cel were similar to ide-cel. CRS occurred in 84% of patients receiving cilta-cel in CARTITUDE-1 and -4 with a median onset of seven days and duration of four days. Grade 3-4 CRS occurred in 4% (4 patients in CARTITUDE-1 and 2 in CARTITUDE-4); Recommendations for treatment mirror ide- cel. ICANS occurred in 13% of all patients, with a median onset of eight days and a duration of six days. Only 2% were grade 3-4. 97% of patients with ICANs had CRS. In CARTITUDE-4 there was a higher number of patients that died in the cilta-cel treatment arm in the first eight weeks compared to the standard of care arm, 22 versus 8 patients. However, none of these patients received cilta-cel prior to their deaths and occurred during the bridging period. It is theorized that the increase in deaths could be attributed to lower doses of pomalidomide and bortezomib administered than would be given during regular treatment cycles. Both ide-cel and cilta-cel have warnings


about early death due to numerically higher deaths in the CAR-T arms versus the standard of care arms during the first 9 to 10 months of therapy. Some of these deaths occurred prior to CAR-T infusion. In KarMMA-3, out of the 45 fatalities reported in the treatment arm, 20 occurred prior to ide-cel infusion. Te remaining 25 deaths were attributed to disease progression (n = 10), adverse events (n = 11), and unknown causes (n = 4). In CARTITUDE-4, out of the 29 reported deaths at 10 months, 10 deaths occurred prior to cilta-cel infusion. Te remaining 19 deaths occurred due to adverse


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